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About the Regulatory Profession

The regulatory function is vital in making safe and effective healthcare products available worldwide. Individuals who ensure regulatory compliance and prepare submissions, as well as those whose main job function is clinical affairs or quality assurance are all considered regulatory professionals.

Regulatory Code of Ethics

One of our most valuable contributions to the profession is the Regulatory Code of Ethics. The Code of Ethics provides regulatory professionals with core values that hold them to the highest standards of professional conduct.

Regulatory Competency Framework

Like all professions, regulatory is based on a shared set of competencies. The Regulatory Competency Framework describes the essential elements of what is required of regulatory professionals at four major career and professional levels.

Regulatory Convergence

Join the brightest minds in regulatory at the annual Regulatory Convergence. See the global regulatory community in action. Intensive workshops. Topical sessions. Meet ups with regulators. This is where it all comes together.

The European Medicines Agency (EMA) on Tuesday published new draft guidance on the evaluation of anticancer medicines in humans that covers all stages of clinical development.

The guidance, which is available for comment through 15 September, delves into the development of treatments for malignancies, including “drug resistance modifiers or normal tissue protective compounds.”

A very large number of anti-cancer compounds are being developed, EMA notes, though only a minority have obtained marketing authorization “due to poor activity or evidence of a detrimental safety profile. Until non-clinical models with good predictive properties have been defined, this situation is likely to remain essentially unchanged and the absence of such models is considered to constitute the greatest hurdle for efficient drug development within the foreseeable future.”

Peter Langecker, contract research organization Clinipace’s Executive Medical Director of Global Oncology, told Focus: "The guidance specifically encourages the development of molecule-specific preclinical models to assess and predict anticipated activity as well as safety and that is now pretty much a standard approach of companies developing these new targeted molecules. This is part of the reason why such deep pockets are needed. The validation and predictive reliability of these models is very work-intensive and you need very experienced tumor immunologists – and that field is rapidly specializing. Companion diagnostics are now standard elements of most new targeted molecules in development."

EMA adds that its aim with the guidance has been to classify compounds according to reasonable designs of exploratory studies, “i.e. cytotoxic compounds where toxicity and ORR [overall response rate] are considered suitable markers of activity in dose finding studies vs. non-cytotoxic compounds where ORR and/or toxicity may not serve this purpose.”

Langecker added: "The guidance has one new element that at least I had not seen before – it suggests intra-patient dose escalation in Phase 1 to allow reaching more effective drug levels as long as there is no toxicity seen in two dosing cycles. That used to be a no-no. That could be useful – a lot of drugs also fail because the Phase 1 takes 3 year. They never get off the ground. This would especially help small biotechs."

Background

An EMA guideline on anticancer medicinal products was first adopted in 1996, and then revised in 2001 and 2003 to focus on conventional cytotoxic compounds.

In 2005, a major revision was undertaken to include more guidance on non-cytotoxic compounds, to expand on the sections on exploratory trials and to provide more guidance on methodological issues.

Later, EMA created an appendix on methodological issues related to use of progression-free survival (PFS) and in early 2010 an appendix on hematological malignancies.

Safety Profile

EMA calls on companies to submit data on overall survival “compatible with a trend towards favorable outcome” so as to capture possible negative effects on the activity of next-line therapies and also treatment-related fatalities.

“This has consequences with respect to interim analyses, other than for futility, and cross-over, which thus should be undertaken only when available survival data provide the information needed for a proper evaluation of benefit/risk,” EMA says.

The agency also notes that the requirements of the characterization of the safety profile have changed with the emergence of molecularly targeted agents (MTAs), immune-modulating drugs and other non-cytotoxic agents. These types of drugs may have other types of toxicity and are often dosed differently than conventional chemotherapy, EMA says, noting that the dose-finding process and concepts such as dose limiting toxicity may need to be addressed differently than for standard cytotoxic agents.

Langecker noted: “The biggest news coming out of the updated EMA guidelines on this topic is the focus on targeted, molecularly-driven compounds and how their development differs from cytotoxic agents, which has been the focus in the past."

That safety focus “has new relevance in the context of Zydelig (Gilead’s PI3K inhibitor), which is being investigated by the EMA for some 3 deaths due to infection,” Langecker added. Gilead earlier this week halted six clinical trials for the drug, which is approved for other indications in the US and EU.

"The targeted treatments specifically inhibit these overexpressed pathways, enzymes, kinases or checkpoints, etc., thereby largely sparing normal cells, while allowing the process of elimination of tumor cells to proceed," he said. "These would be apoptosis, or activation of specific T-cells or – like in the case of PD-1/PD-L1, removing the brakes from the immune system to enable the attack on malignant transformed cancer cells (think of pulling the invisibility cloth from Harry Potter). As long as these targeted processes are expressed by the tumor these drugs or biologics work fine. Often, however, cancers develop alternate pathways, hence the need for a broad array of these targeted agents that are then deployed in sequence or in combination to enhance their effects."

EMA adds in its latest guidance: “Cumulative incidences by toxicity grade are not sufficient to characterize the toxicity profile. The impact of an adverse drug reaction (ADR) on the benefit-risk balance may for example differ importantly depending on how the incidence, prevalence and severity change with time on treatment, and on the possibility to alleviate the ADR by dose reduction.”

General Recommendations

In addition to defining the proper dose(s) and schedule(s) of a cancer drug, EMA stresses the importance of identifying a target population with optimized benefit/risk in the section on exploratory studies.

Guidance is also provided on studies for combinations of drugs with minimal activity as monotherapies, but “synergistic effects when combined, as well as combinations of conventional cytotoxics.”

And although EMA does not include a precise definition of “trend towards favorable effects on survival” or “reasonably excluding negative effects on OS,” the agency notes that if a major increase in toxicity is foreseeable, it is recommended that confirmatory studies are undertaken with the aim to show an OS benefit. It is also acknowledged that improved safety without loss in efficacy may constitute tangible aims and the design of non-inferiority efficacy studies.